The long-term objective of our research is to characterize the molecular and genetic role of GCM2 in controlling parathyroid gland development during embryogenesis and parathyroid cell maintenance after birth. Studies in mice have shown that parathyroid formation is under the control of the Gcm2 gene (glial cell missing 2), which encodes a novel transcription factor that is expressed exclusively in the developing and mature parathyroid gland. Studies from our laboratory and by others have shown that genetic mutations that inactivate GCM2 in humans cause hypoparathyroidism, a metabolic disorder characterized by severe hypocalcemia and hyperphosphatemia due to deficiency of parathyroid hormone (PTH). Genetic ablation of Gcm2 in mouse embryos causes a similar phenotype with parathyroid aplasia. These observations establish GCM2 as the master control gene for embryological development of parathyroid glands, but leave unanswered questions about the role of Gcm2 during late gestation and during postnatal life. We hypothesize that expression of Gcm2 in the parathyroid is necessary throughout life to maintain parathyroid cell mass, and that lack of Gcm2 will induce parathyroid cell death. We propose to use mouse models that we have developed that enable us to genetically delete the Gcm2 gene conditionally, in a temporally and spatially controlled manner, to identify the genes that are controlled by Gcm2 action and the effect of loss of Gcm2 on growth and function of mature parathyroid cells. Mice with conditional Gcm2 alleles will also allow us to determine whether ablation of Gcm2 late in life can "rescue" mice that have parathyroid disorders that replicate the human condition primary hyperparathyroidism. The specific aims of this proposal are: 1. to characterize our mice with conditional Gcm2 alleles; 2. to determine the consequences of timed deletion of Gcm2 on parathyroid cell growth and function in normal mice and mice with parathyroid hyperplasia; and 3. to identify genes that are controlled by Gcm2, using a combination of microarray expression analysis and chromatin immunoprecipitation. Together, these experiments will elucidate the role of GCM2 in regulating parathyroid growth and development across the lifespan, and provide critical new information regarding the genes that are regulated by Gcm2. Ultimately, this information may yield new strategies for regulating parathyroid growth and/or function in patients with parathyroid disorders.

The parathyroid glands synthesize and secrete parathyroid hormone, the principal regulator of bone and mineral metabolism. We now know that embryological development of the parathyroid gland is under the control of a key regulatory gene, GCM2, and that defects in this gene lead to hypoparathyroidism, an endocrine disorder in which blood calcium levels are very low due to absence or deficiency of parathyroid hormone. This research project proposes experiments that will extend our knowledge of the role of GCM2 in controlling parathyroid cell growth and function in health and disease, and which ultimately may have applicability in the treatment of patients who have parathyroid disorders.